Therapeutic agent for renal failure

ABSTRACT

The present invention relates to a therapeutic agent for renal failure comprising, as an active ingredient, a 4,8-inter-m-phenylene prostaglandin I 2  derivative, and also relates to a method of treatment of renal failure using the same.

TECHNICAL FIELD

[0001] The present invention relates to a therapeutic agent for renalfailure comprising, as an active ingredient, a 4,8-inter-m-phenyleneprostaglandin I₂ derivative or a pharmacologically acceptable saltthereof.

BACKGROUND ART

[0002] Prostaglandins (PGs) are a class of naturally occurring compoundswith a wide variety of physiological activities, which have a commonprostanoic acid skeleton. Naturally occurring PGs are classified intoPGAs, PGBs, PGCs, PGDs, PGEs, PGFs, PGGs, PGHs, PGIs and PGJs accordingto the structural characteristics of the 5-membered ring in theskeleton. It is and also classified into subclasses 1, 2, 3 and so onaccording to the ansaturation and oxidation. Various synthetic analoguesof these PGs are known. Among these, PGI₂, which is a typical PGIderivative, is called prostacycline (see Nature, vol. 268, p. 688,1976). PGI₂ is known as a substance having potent platelet aggregationinhibiting activity and peripheral vasodilator activity. JapaneseExamined Patent Application Publication Nos. 2-12226, 2-57548 and1-53672 have described 4,8-inter-m-phenylene PGI₂ derivatives, in whichthe exo-enol ether moiety that is a structurally characteristic portionof PGI₂ is converted to an inter-m-phenylene moiety to substantiallyimprove the instability of PGI₂. However, it has not yet recognized thatsuch derivatives have therapeutic activities on renal failure.

[0003] Renal failure is a condition characterized by decreased number offunctional nephrons, resulting in reduced excretion of nitrogenousmetabolic products and eventually causing the failure to maintainhomeostasis in the biological environment. Specifically, this can besaid to be a condition in which blood urea nitrogen (BUN) and creatininelevels are continuously increased. Renal failure is categorized into twoprimary types: acute renal failure in which the onset is abrupt andrecovery may occur; and chronic renal failure which is slowlyprogressive but irreversible.

[0004] Acute renal failure is primarily categorized into the followingtwo types: oliguric acute renal failure which is frequently complicatedby water, electrolyte and acid-base imbalances and manifested byoliguria or anuria; and non-oliguric acute renal failure in whichdecreased urinary volume is not found.

[0005] Acute renal failure is also categorized into the following threetypes according to its cause: 1) pronephric acute renal failure in whichreduction of renal blood flow occurs due to systemic hemodynamic changessuch as prerenal dehydration and shock, causing reduced glomerularfiltration rate; 2) renal acute renal failure which is induced byglomerular and tubular disorders such as acute tubular necrosis; and 3)postrenal acute renal failure which is caused by obstruction of theurinary tract, e.g., by a calculus. According to the clinicalmanifestations, it can also be categorized into oliguric, uretic andrecovery stages. In the treatment of acute renal failure, it isimportant to track down its cause and sufficiently perform systemiccontrol of the patient. Such treatment includes two major forms,conservative treatment and dialytic treatment. According to theconservative treatment, in the oliguric stage, excessive water drinkingis avoided and the amount of protein intake is restricted, whilesimultaneously supplying a sufficient amount of calories. In theoliguric stage, or when heart failure has occurred, then sodium intakeis restricted. In contrast, in the uretic stage, potassium intake isincreased. Generally in the oliguric stage, calcium intake isrestricted. In the case where BUN is 60 mg/dl or higher or rises by 30mg/dl or more per day or hyperkalemia or heart failure is found, then itis recommended to perform an early frequent dialysis.

[0006] Chronic renal failure is a condition in which gradual reductionin renal functions occurs due to a chronically progressive renaldisease, in which the reduced renal functions are manifested as theinsufficiency of all functions for which the normal kidney isresponsible. The causal diseases of chronic renal failure are all of thenephropathic diseases, including primary renal diseases, nephropathy insystemic diseases, congenital renal diseases, renal infections,nephropathy induced by any nephrotoxic substance and obstructive urinarydiseases. As seen in the clinical background of patients to whomdialysis has been introduced for treatment of chronic renal failure, theprimary causal diseases of chronic renal failure may include chronicglomerulonephritis, diabetic nephropathy, chronic pyelonephritis,nephrosclerosis and cystic kidney. Among these, chronicglomerulonephritis and diabetic nephropathy make up a large proportion.The proportion of diabetic nephropathy as the causal disease in thetotal cases, however, remarkably increases as the number of diabeticpatients rapidly increases in recent years.

[0007] As stated above, renal failure may be caused by various diseases.However, all types of renal failure have particular common clinicalmanifestations regardless of their causal diseases, such as lungcongestion and congestive heart failure associated with reduced urinaryvolume; neurological or mental complaints associated with advanceduremia; anemia caused by reduced production of erythropoietin in thekidney; electrolyte imbalance, such as hyponatremia and hyperkalemia;gastrointestinal complaints; defect of bone metabolism; and defect ofcarbohydrate metabolism.

[0008] For the treatment of chronic renal failure in the conservativestage, dietary therapy including a low-protein, high-calorie diet isbasically employed. In this case, it is required to restrict sodiumchloride intake and water intake and to use an antihypertensive agent tocontrol the hypertention which may be a risk factor for exacerbation ofrenal failure. However, such dietary therapy and the treatment with anantihypertensive agent as mentioned above produce unsatisfactoryeffects. Therefore, the number of patients who inevitably havehemodialysis goes on increasing year by year due to the manifestation ofuremic symptoms caused by the advanced disorders of renal functions. Inpatients with renal failure who have entered into dialysis, remarkableimprovement in the rate of prolongation of life has been achieved due tothe improved hemodialysis therapy in recent years. However, there stillremain problems in that the patients are unavoidable to visit thehospital twice or three times a week, that defects of erythrocyteproduction or maturation may occur, that complications will follow whichmay caused by the accumulation of aluminum and β2-microglobulin in abody occurring after the long-term dialysis, and so on.

[0009] The object of the present invention is to provide a therapeuticagent for renal failure on which already-existing drugs or agents showunsatisfactory effects.

DISCLOSURE OF INVENTION

[0010] The present invention provides a therapeutic agent for renalfailure comprising, as an active ingredient, a 4,8-inter-m-phenyleneprostaglandin I₂ derivative or a pharmacologically acceptable saltthereof.

BEST MODE OF CARRYING OUT THE INVENTION

[0011] The 4,8-inter-m-phenylene prostaglandin I₂ derivative accordingto the present invention is represented by the following formula (I):

[0012] wherein:

[0013] R¹ represents:

[0014] (A) COOR²

[0015] wherein R² represents:

[0016] 1) hydrogen or a pharmacologically acceptable positive ion;

[0017] 2) a straight-chain C₁₋₁₂ alkyl group or a branched C₃₋₁₄ alkylgroup;

[0018] 3) -Z-R³

[0019] wherein Z represents a valence bond or a straight-chain orbranched alkylene group represented by C_(t)H_(2t) where t represents aninteger from 1 to 6; and R³ represents a C₃₋₁₂ cycloalkyl groupunsubstituted or substituted by 1 to 3 substituents of R⁴ where R⁴ ishydrogen or a C₁₋₅ alkyl group;

[0020] 4) —(CH₂CH₂O)_(n)CH₃

[0021] wherein n represents an integer from 1 to 5;

[0022] 5) -Z-Ar¹

[0023] wherein Z has the same meaning as defined above; and Ar¹represents phenyl, α-naphthyl, β-naphthyl, 2-pyridyl, 3-pyridyl,4-pyridyl, α-furyl, β-furyl, α-thienyl, β-thienyl or substituted phenyl(wherein the substituted phenyl contains at least one substituent ofchlorine, bromine, fluorine, iodine, trifluoromethyl, a C₁₋₄ alkylgroup, nitro, cyano, methoxy, phenyl, phenoxy, p-acetamidobenzamide,—CH═N—NH—C(═O)—NH₂, —NH—C(═O)-Ph, —NH—C(═O)—CH₃ or —NH—C(═O)—NH₂);

[0024] 6) —C_(t)H_(2t)COOR⁴

[0025] wherein each of C_(t)H_(2t) and R₄ has the same meaning asdefined above;

[0026] 7) —C_(t)H_(2t)N(R⁴)₂

[0027] wherein each of C_(t)H_(2t) and R₄ has the same meaning asdefined above;

[0028] 8) —CH(R⁵)—C(═O)—R⁶,

[0029] wherein R⁵ represents hydrogen or benzoyl; and R⁶ representsphenyl, p-bromophenyl, p-chlorophenyl, p-biphenyl, p-nitrophenyl,p-benzamidophenyl or 2-naphthyl;

[0030] 9) —C_(p)H_(2p)—W—R⁷

[0031] wherein W represents —CH═CH—, —CH═CR⁷— or —C≡C—; R⁷ representshydrogen or a straight-chain or branched C₁₋₃₀ alkyl or aralkyl group;and p represents an integer from 1 to 5; or

[0032] 10) —CH(CH₂OR⁸)₂

[0033] wherein R⁸ represents a C₁₋₃₀ alkyl or acyl group;

[0034] (B) —CH₂OH;

[0035] (C) —C(═O)N(R⁹)₂

[0036] wherein R⁹ represents hydrogen or a straight-chain C₁₋₁₂ alkylgroup, a branched C₃₋₁₂ alkyl group, a C₃₋₁₂ cycloalkyl group, a C₄₋₁₃cycloalkylalkylene group, a phenyl group, a substituted phenyl group(wherein the substitute or substituents are the same radicals as definedfor (A)-5) described above), a C₇₋₁₂ aralkyl group, or —SO₂R¹⁰ where R¹⁰represents a C₁₋₁₀ alkyl group, a C₃₋₁₂ cycloalkyl group, a phenylgroup, a substituted phenyl group [wherein the substitute orsubstituents are the same radicals as defined for (A)-5] describedabove] or a C₇₋₁₂ aralkyl group; provided that the two R⁹ radicals arethe same as or different from each other, but when one represents—SO₂R¹⁰, then the other does not represent —SO₂R¹⁰; or

[0037] (D) —CH₂OTHP (wherein THP represents a tetrahydropyranyl group);

[0038] A represents:

[0039] 1) —(CH₂)_(m)—;

[0040] 2) —CH═CH—CH₂—;

[0041] 3) —CH₂—CH═CH—;

[0042] 4) —CH₂—O—CH₂—;

[0043] 5) —CH═CH—;

[0044] 6) —O—CH₂—; or

[0045] 7) —C≡C—

[0046] wherein m represents an integer from 1 to 3; Y representshydrogen, a C₁₋₄ alkyl group, chlorine, bromine, fluorine, formyl,methoxy or nitro group; B represents —X—C(R¹¹)(R¹²)OR¹³

[0047] wherein:

[0048] R¹¹ represents hydrogen or a C₁₋₄ alkyl group;

[0049] R¹³ represents hydrogen, a C₁₋₁₄ acyl group, a C₆₋₁₅ aroyl group,tetrahydropyranyl, tetrahydrofuranyl, 1-ethoxyethyl or t-butyl;

[0050] X represents:

[0051] 1) —CH₂—CH₂—;

[0052] 2) —CH═CH—; or

[0053] 3) —C≡C—; and

[0054] R¹² represents:

[0055] 1) a straight-chain C₁₋₁₂ alkyl group or a branched C₃₋₁₄ alkylgroup;

[0056] 2) -Z-Ar²;

[0057] wherein Z has the same meaning as defined above; and Ar²represents phenyl, α-naphthyl, β-naphthyl, or at least one chlorine,bromine, fluorine, iodine, trifluoromethyl, a C₁₋₄ alkyl group, nitro,cyano, methoxy, phenyl or phenoxy-substituted phenyl, or

[0058] 3) —C_(t)H_(2t)OR¹⁴;

[0059] wherein C_(t)H_(2t) has the same meaning as defined above; andR¹⁴ represents a straight-chain C₁₋₆ alkyl group, a branched C₃₋₆ alkyl,phenyl, or at least one chlorine, bromine, fluorine, iodine,trifluoromethyl, an C₁₋₄ alkyl, nitro, cyano, methoxy, phenyl orphenoxy-substituted phenyl, cyclopentyl, cyclohexyl, or a cyclopentyl orcyclohexyl substituted by 1 to 4 straight-chain C₁₋₄ alkyl groups;

[0060] 4) -Z-R³

[0061] wherein each of Z and R³ has the same meaning as defined above;

[0062] 5) —C_(t)H_(2t)—CH═C(R¹⁵)R¹⁶

[0063] wherein C_(t)H_(2t) has the same meaning as defined above; andR¹⁵ and R¹⁶ independently represent hydrogen, methyl, ethyl, propyl orbutyl group; or

[0064] 6) —C_(u)H_(2u)—C≡C—R¹⁷

[0065] wherein u represents an integer from 1 to 7; C_(u)H_(2u)represents a straight-chain or branched alkylene group; and R¹⁷represents a straight-chain C₁₋₆ alkyl group; and E represents hydrogenor —OR¹⁸

[0066] wherein R¹⁸ represents a C₁₋₁₂ acyl group, a C₇₋₁₅ aroyl group orR² (wherein R² has the same meaning as defined above); and the formulais in the isomeric d-form, l-form or dl-form.

[0067] The therapeutic agent for renal failure according to the presentinvention comprises, as an active ingredient, a 4,8-inter-m-phenyleneprostaglandin I₂ derivative represented by the formula (I) above or apharmacologically acceptable salt thereof.

[0068] Among the 4,8-inter-m-phenylene prostaglandin I₂ derivativesdescribed above, those derivatives described below and pharmacologicallyacceptable salt thereof are preferably used which are represented by theformula (I) above wherein:

[0069] R¹ represents COOR² wherein R² represents hydrogen or apharmacologically acceptable positive ion;

[0070] A represents:

[0071] 1) —(CH₂)m—; or

[0072] 2) —CH₂—CH═CH—

[0073] wherein m represents an integer from 1 to 3;

[0074] Y represents hydrogen;

[0075] B represents —X—C(R¹¹)(R¹²)OR¹³

[0076] wherein each of R¹¹ and R¹³ represent hydrogen;

[0077] X represents:

[0078] 1) —CH═CH—; or

[0079] 2) —C≡C—; and

[0080] R¹² represents:

[0081] 1) -Z-Ar²;

[0082] 2) -Z-R³; or

[0083] 3) —C_(u)H_(2u)—C≡C—R¹⁷

[0084] wherein Z represents a valence bond or a straight-chain orbranched alkylene group represented by C_(t)H_(2t) where t represents aninteger from 1 to 6; Ar² represents phenyl, α-naphthyl, β-naphthyl, orat least one chlorine, bromine, fluorine, iodine, trifluoromethyl, aC₁₋₄ alkyl group, nitro, cyano, methoxy, phenyl or phenoxy-substitutedphenyl; R³ represents a C₃₋₁₂ cycloalkyl group; u represents an integerfrom 1 to 7; C_(u)H_(2u) represents a straight-chain or branchedalkylene group; and R¹⁷ represents a straight-chain C₁₋₆ alkyl group;and

[0085] E represents —OH. A particularly preferable derivative isberaprost sodium having the following formula.

[0086] The 4,8-inter-m-phenylene prostaglandin I₂ derivative of thepresent invention can be produced by any known process. For example, acompound represented by the formula (I) above or a salt thereof may beproduced according to the process described in Japanese Examined PatentApplication Publication No. 1-53672.

[0087] In the present invention, the 4,8-inter-m-phenylene prostaglandinI₂ derivative can be administered at a dose of 0.001 to 1000 mg peradult subject once to three times a day.

[0088] The therapeutic agent for renal failure of the present inventionmay comprise the derivative alone or a combination of plural types ofthe derivatives and may be administered as is. Alternatively, thetherapeutic agent may be administered orally in the form of a solidpreparation containing an additive or additives shown below.

[0089] The causal disease of renal failure to be treated in the presentinvention may include all of the nephropathic diseases, such as primaryrenal diseases, nephropathies in systemic diseases, congenital renaldiseases, renal infections, nephropathies induced by any nephrotoxicsubstance and obstructive urinary diseases. Specific examples of thecausal disease include, but are not limited to, chronicglomerulonephritis, diabetic nephropathy, chronic pyelonephritis, acuteprogressive nephritis, gestosis, cystic kidney, nephrosclerosis,malignant hypertension, nephropathies accompanied by various collagendiseases such as SLE, amyloid kidney, gouty kidney, disbolic renalfailure, tuberculosis, renal calculosis, malignant tumor in the kidneyand urinary tracts, obstructive urinary tract diseases, myeloma andrenal hypoplasia.

[0090] The renal failure to be treated with the therapeutic agent of thepresent invention is not particularly limited to either of acute orchronic type. However, the therapeutic agent is especially effective onchronic renal failure for which no effective therapy has currently beenestablished and can delay the entrance into dialysis. Even when enteredinto dialysis, the therapeutic agent may be effective for thepreservation of functions of the remained kidney.

[0091] The additive may include excipients, such as starches, lactose,sucrose, glucose, mannitol, calcium carbonate and calcium sulfate;binders, such as starches, dextrin, gum arabic, gum tragacanth, methylcellulose, gelatin, polyvinyl pyrrolidone and polyvinyl alcohol;disintegrating agents, such as starches, polyvinyl pyrrolidone andcrystalline cellulose; lubricants, such as magnesium stearate and talk;coloring agents; flavoring agents; and so on.

[0092] The 4,8-inter-m-phenylene prostaglandin I₂ derivative to be usedin the present invention may be administered in various dosage forms.Specifically, the dosage form may be any conventional one, such astablets, dragees, powders, granules, troches, capsules, pills, syrup andspray.

[0093] The derivative may also be administered parentally in the form ofa sterile solution. Sodium chloride, glucose or any other solute may beadded to the solution, for example, in the amount sufficient to make thesolution isotonic.

[0094] In addition to the dosage form for oral administration mentionedabove, the therapeutic agent for renal failure of the present inventionmay be prepared in various dosage forms, such as various types ofinjections and suppositories for parenteral administration.

EXAMPLES

[0095] The present invention will be described more in detail withreference to the following examples.

Example 1

[0096] Effect of beraprost sodium on ⅚ nephrectomized rat model:

[0097] The effect of beraprost sodium on a ⅚ nephrectomized rat model,which has been widely used as a model animal for renal failure, wasexamined. Two-thirds of the left kidney was removed from each of4-week-old male Wistar rats (Charles River Japan Inc.) with a razor, andall of the right kidney was then removed therefrom one week after. Threeweeks after the initial surgery, blood was collected from each ratthrough the tail vein and serum creatinine and BUN levels weredetermined from the blood. At this point of time, the urine was alsocollected for 24 hours to determine the mass of proteins in the urine.The rats were allocated to one of the treatment groups by thestratifying continuous randomization method based on the mass ofproteins in the urine and the body weight (n=8 per group). There wasobserved little difference in the initial values of blood creatinine andBUN values among the rats. Three weeks after the initial surgery,beraprost sodium or captopril (SIGMA, i.e., a positive control) wasorally administered to each rat twice a day everyday, beginning the dayon which administration of a drug was started and continued through fiveweeks after the administration. The determination of the renal functionswas performed both three weeks and five weeks after the initialadministration of a drug. The photographic images of the renal tissuewere observed only five weeks after the initial administration. In thesham surgery group (“sham”) in which no drug was administered, increasedBUN level (which is a measure of the progress of chronic renal failure)was observed three weeks after the initial administration, whichindicated that chronic renal failure was advanced. Five weeks after theinitial administration, more exacerbation of chronic renal failure wasobserved. In the beraprost sodium-administered group, significantprevention of increase in the urinary protein level and prevention ofreduction in the creatinine clearance and increase in the BUN level wereobserved three weeks after the initial administration (Table 1). Thesame tendency was shown five weeks after the initial administration(Table 2). As demonstrated by the observation of renal tissue imagesfive weeks after the initial administration, the progress of theglomerular conditions was markedly prevented (Table 3). In the positivecontrol group (i.e., the captopril-administered group), the similarameliorative effects were shown. These results clearly demonstrate thatberaprost sodium can improve the conditions of renal failure rats. TABLE1 Effect of beraprost on chronic renal failure model rats (three weeksafter the administration of a drug) Urinary Blood Urinary proteinCreatinine urea Body volume excretion clearance nitrogen Drug weight (g)(ml/24 hr) (mg/24 hr/kgBW) (μl/min/100 gBW) (μg/dl) Sham 229.4 ± 6.132.3 ± 3.7  3.6 ± 0.6 430.9 ± 15.3 14.9 ± 1.1 Control 224.8 ± 6.9 18.4 ±1.7** 320.6 ± 69.7** 132.7 ± 19.9** 58.9 ± 7.7** Captopril 220.6 ± 5.421.7 ± 3.7 136.8 ± 29.9 151.9 ± 12.3 51.4 ± 3.7 (50 mg/kg) TRK-100 215.5± 5.3 20.1 ± 2.8 125.3 ± 20.8^(#) 134.1 ± 11.0 55.9 ± 3.7 (100 μg/kg)TRK-100 221.0 ± 6.3 20.4 ± 3.7 154.4 ± 53.0^(#) 136.4 ± 9.9 50.9 ± 3.6(300 μg/kg)

[0098] TABLE 2 Effect of beraprost on chronic renal failure model rats(five weeks after the administration of a drug) Urinary Blood Urinaryprotein Creatinine urea Body volume excretion clearance nitrogen Drugweight (g) (ml/24 hr) (mg/24 hr/kgBW) (μl/min/100 gBW) (μg/dl) Sham238.4 ± 7.1 24.7 ± 4.1  7.8 ± 0.7 365.6 ± 20.1 16.9 ± 1.1 Control 237.2± 8.1 22.1 ± 3.6 301.4 ± 51.6** 135.4 ± 22.9** 55.2 ± 9.7** Captopril236.4 ± 5.7 21.9 ± 3.2 255.5 ± 76.6 161.1 ± 17.3 47.8 ± 5.2 (50 mg/kg)TRK-100 228.7 ± 5.7 21.7 ± 3.1 276.5 ± 69.2 156.9 ± 19.5 45.5 ± 3.3 (100μg/kg) TRK-100 245.8 ± 8.0 20.4 ± 1.7 197.1 ± 21.1 143.5 ± 10.0 45.1 ±3.5 (300 μg/kg)

[0099] TABLE 3 Captopril (50 BPS BPS Region Histopathological changeSham Control μg/kg) (100 μg/kg) (300 μg/kg) Renal corpuscle Glomerularhypertrophy 0 8 1 3 2 Cellular filling in glomerulus 0 7 4 7 4Glomerulosclerosis 0 3 2 2 1 Epidermal growth in Bowman's capsule 0 5 21 1 Deposition of PAS + materials in 0 3 1 2 1 Bowman's capsuleCoagulation of glomeruli in Bowman's 0 5 2 2 1 capsule UriniferousBasophilic degeneration of tubules 0 8 6 8 8 tuble Proliferation ofproximal tubules 0 8 8 8 8 Tubular dilation 0 8 8 8 8 Proteinaceousurinary casts 0 8 4 5 2 Framework Infiltration of mononuclear cells 0 67 7 7

Example 2

[0100] Renal failure rat models of which the primary disease wasglomerulonephritis were used to examine the effect of different4,8-inter-m-phenylene prostaglandin I₂ derivatives including beraprostsodium on the models. Eight-week-old male WKY rats (Charles River JapanInc.) were administered intravenously with rabbit anti-rat glomerularbasement membrane antiserum to induce glomerulonephritis. Two weeksafter the induction, blood was collected from each rat through the tailvein to determine blood creatinine and BUN levels. The blood creatinineand BUN levels in the glomerulonephritis-induced rats were remarkablyhigher than those in the non-induced rats, which indicated that theconditions of the rats progressed into renal failure. Four types of4,8-inter-m-phenylene prostaglandin I₂ derivatives in total, includingberaprost sodium, were individually administered subcutaneously to therats from the back continuously with an osmotic pump (ALZET) for oneweek, beginning two weeks after induction of glomerulonephritis andcontinued through three weeks after the induction. The renal functions(i.e., blood creatinine and BUN levels) were determined one week afterthe initial administration of a drug. In a glomerulonephritis-inducedgroup to which no drug was administered (i.e., a control group), bloodcreatinine and the BUN levels determined three weeks after the inductionof glomerulonephritis were increased compared with those determined twoweeks after the induction, which indicated that the conditions of therats progressed into chronic renal failure. In a beraprostsodium-administered group, blood creatinine and BUN levels determinedthree weeks after the induction of glomerulonephritis were significantlydecreased compared with those in the control group (Table 4). In groupsto which other three types of 4,8-inter-m-phenylene prostaglandin I₂derivatives (i.e., compounds 1, 2 and 3 shown below) were respectivelyadministered, the similar ameliorative effect was observed (Table 5).

[0101] These results indicate that the 4,8-inter-m-phenyleneprostaglandin I₂ derivatives including beraprost sodium can improve theconditions of rats with renal failure. TABLE 4 Effect of beraprostsodium on renal failure rat models of which the primary disease isglomerulonephritis Blood creatinine (mg/dl) BUN (mg/dl) 3 weeks after 3weeks after 2 weeks after induction 2 weeks after induction induction (1week after induction (1 week after (before the initial (before theinitial admini- admini- admini- admini- stration) stration) stration)stration) Normal 0.32 ± 0.02 0.30 ± 0.01 11 ± 1 18 ± 1 group Control0.64 ± 0.09* 0.89 ± 0.12* 33 ± 7* 40 ± 3* group Beraprostsodium-administered group 60 μg/kg 0.61 ± 0.07* 0.48 ± 0.04# 28 ± 3* 31± 2 # 200 0.62 ± 0.06* 0.49 ± 0.04# 30 ± 3* 25 ± 1# μg/kg

[0102] TABLE 5 Effect of different 4,8-inter-m-phenylene prostaglandinI₂ derivatives on renal failure rat models of which the primary diseaseis glomerulonephritis Blood creatinine (mg/dl) BUN (mg/dl) 3 weeks after3 weeks after 2 weeks after induction 2 weeks after induction induction(1 week after induction (1 week after (before the initial (before theinitial admini- admini- admini- admini- stration) stration) stration)stration) Normal 0.30 ± 0.02 0.29 ± 0.02 19 ± 1 19 ± 1 group Control0.44 ± 0.03* 0.65 ± 0.04* 28 ± 2* 44 ± 2* group 4,8-inter-m-phenyleneprostaglandin I₂ derivative-administered group Compound 0.44 ± 0.05*0.41 ± 0.02# 29 ± 2* 27 ± 2# 1 60 μg/kg Compound 0.45 ± 0.04* 0.44 ±0.05# 28 ± 2* 31 ± 3# 2 60 μg/kg Compound 0.45 ± 0.05* 0.39 ± 0.04# 28 ±3* 30 ± 3# 3 60 μg/kg

Example 3

[0103] Glomerulonephritis rat models were used to examine the effect ofberaprost sodium on the rat models both in a stage where renal failurehad not been found (i.e., the inflammatory stage) and a stage where BUNlevel was increased and the conditions were progressed into renalfailure (i.e., the renal failure stage). Eight-week-old male WKY rats(Charles River Japan Inc.) were administered intravenously with rabbitanti-rat glomerular basement membrane antiserum to induceglomerulonephritis. Each of beraprost sodium, captopril (SIGMA) andprednisolone (Shionogi & Co., Ltd.) was orally administered to the ratseveryday either for one week from day 1 through day 7 after induction ofglomerulonephritis (i.e., during the inflammatory stage) or for twoweeks beginning two weeks after the induction through four weeks afterthe induction (i.e., during the renal failure stage). The frequency ofthe administration was twice a day for beraprost sodium and captopriland once a day for prednisolone. After the initial administration of adrug, urinary total protein excretion (which is a measure of renalfunctions) was determined. In the inflammatory stage (i.e., from day 1through day 7 after induction of glomerulonephritis), the urinary totalprotein excretion in a glomerulonephritis-induced group to which no drugwas administered (i.e., a control group) was remarkably increasedcompared with that in a non-glomerulonephritis-induced group (i.e., anormal group) (Table 6). In a beraprost sodium-administered group, theincrease in urinal total protein excretion was markedly prevented (Table6). In both captopril- and prednisolone-administered groups, effectiveprevention of increase in urinal total protein excretion was observed(Table 6). On the other hand, in the renal failure stage (i.e., from twoweeks after induction of glomerulonephritis through four weeks after theinduction), the urinary total protein excretion in theglomerulonephritis-induced group without administration of a drug (i.e.,the control group) was remarkably increased compared with that in anon-glomerulonephritis-induced group (i.e., a normal group); incontrast, in the beraprost sodium-administered group, the increase inurinal total protein excretion was markedly prevented (Table 6). In boththe captopril- and prednisolone-administered groups, no effectiveprevention of increase in urinal total protein excretion was observed(Table 6).

[0104] These results indicate that both prednisolone and captopril arenot effective on the rats in the renal failure stage although they areeffective on the rats in the inflammatory stage. In contrast, it isclearly indicated that beraprost sodium can improve the conditions ofthe rats both in the inflammatory stage and the renal failure stage.TABLE 6 Effect of beraprost sodium, captopril and prednisolone onglomuerulonephritis model rats in inflammatory and renal failure stagesUrinary total protein excretion (mg/24 hr) Inflammatory Renal failurestage stage Exp. 1 Exp. 2 7 days after 3 weeks after induction 2 weeksafter induction 2 weeks after (1 week after induction (1 week afterinduction 4 weeks after induction initial (before initial (before (2week after initial administration administration) administration)administration) administration) Normal  19 ± 1  30 ± 6  20 ± 2  14 ± 1 17 ± 1 group Control 138 ± 9* 370 ± 30* 423 ± 55* 324 ± 18* 451 ± 77*group Beraprost-administered group 300 μg/kg  17 ± 7# 374 ± 21* 300 ±51# 321 ± 23* 295 ± 46# Captopril-administered group  50 mg/kg  75 ± 14#N.D. N.D. 318 ± 22* 504 ± 51 100 mg/kg N.D. N.D. N.D. 325 ± 6* 517 ± 33Prednisolone-administered group  2 mg/kg  38 ± 8# 368 ± 20 456 ± 78 N.D.N.D.

Industrial Applicability

[0105] The present invention provides a therapeutic agent for renalfailure comprising, as an active ingredient, a 4,8-inter-m-phenyleneprostaglandin I₂ derivative.

1. A therapeutic agent for renal failure comprising, as an activeingredient, a 4,8-inter-m-phenylene prostaglandin I₂ derivativerepresented by the following formula (I) or a pharmacologicallyacceptable salt thereof:

wherein: R¹ represents: (A) COOR² wherein R² represents: 1) hydrogen ora pharmacologically acceptable positive ion; 2) a straight-chain C₁₋₁₂alkyl group or a branched C₃₋₁₄ alkyl group; 3) -Z-R³ wherein Zrepresents a valence bond or a straight-chain or branched alkylene grouprepresented by C_(t)H_(2t) where t represents an integer from 1 to 6;and R³ represents a C₃₋₁₂ cycloalkyl group unsubstituted or substitutedby 1 to 3 substituents of R⁴ where R⁴ is hydrogen or a C₁₋₅ alkyl group;4) —(CH₂CH₂O)_(n)CH₃ wherein n represents an integer from 1 to 5; 5)-Z-Ar¹ wherein Z has the same meaning as defined above; and Ar¹represents phenyl, α-naphthyl, β-naphthyl, 2-pyridyl, 3-pyridyl,4-pyridyl, α-furyl, β-furyl, α-thienyl, β-thienyl or substituted phenyl(wherein the substituted phenyl contains at least one substituent ofchlorine, bromine, fluorine, iodine, trifluoromethyl, a C₁₋₄ alkylgroup, nitro, cyano, methoxy, phenyl, phenoxy, p-acetamidobenzamide,—CH═N—NH—C(═O)—NH₂, —NH—C(═O)-Ph, —NH—C(═O)—CH₃ or —NH—C(═O)—NH₂); 6)—C_(t)H_(2t)COOR⁴ wherein each of C_(t)H_(2t) and R⁴ has the samemeaning as defined above; 7) —C_(t)H_(2t)N(R⁴)₂ wherein each ofC_(t)H_(2t) and R⁴ has the same meaning as defined above; 8)—CH(R⁵)—C(═O)—R⁶, wherein R⁵ represents hydrogen or benzoyl; and R⁶represents phenyl, p-bromophenyl, p-chlorophenyl, p-biphenyl,p-nitrophenyl, p-benzamidophenyl or 2-naphthyl; 9) —C_(p)H_(2p)—W—R⁷wherein W represents —CH═CH—, —CH═CR⁷— or —C≡C—; R⁷ represents hydrogenor a straight-chain or branched C₁₋₃₀ alkyl or aralkyl group; and prepresents an integer from 1 to 5; or 10) —CH(CH₂OR⁸)₂ wherein R⁸represents a C₁₋₃₀ alkyl or acyl group; (B) —CH₂OH; (C) —C(═O)N(R⁹)₂wherein R⁹ represents hydrogen or a straight-chain C₁₋₁₂ alkyl group, abranched C₃₋₁₂ alkyl group, a C₃₋₁₂ cycloalkyl group, a C₄₋₁₃cycloalkylalkylene group, a phenyl group, a substituted phenyl group(wherein the substitute or substituents are the same radicals as definedfor (A)-5) described above), a C₇₋₁₂ aralkyl group, or —SO₂R¹⁰ where R¹⁰represents a C₁₋₁₀ alkyl group, a C₃₋₁₂ cycloalkyl group, a phenylgroup, a substituted phenyl group (wherein the substitute orsubstituents are the same radicals as defined for (A)-5) describedabove) or a C₇₋₁₂ aralkyl group; provided that the two R⁹ radicals arethe same as or different from each other, but when one represents—SO₂R¹⁰, then the other does not represent —SO₂R¹⁰; or (D) —CH₂OTHP(wherein THP represents a tetrahydropyranyl group); A represents: 1)—(CH₂)_(m)—; 2) —CH═CH—CH₂—; 3) —CH₂—CH═CH—; 4) —CH₂—O—CH₂—; 5) —CH═CH—;6) —O—CH₂—; or 7) —C≡C— wherein m represents an integer from 1 to 3; Yrepresents hydrogen, a C₁₋₄ alkyl group, chlorine, bromine, fluorine,formyl, methoxy or nitro group; B represents —X—C(R¹¹)(R¹²)OR¹³ wherein:R¹¹ represents hydrogen or a C₁₋₄ alkyl group; R¹³ represents hydrogen,a C₁₋₁₄ acyl group, a C₆₋₁₅ aroyl group, tetrahydropyranyl,tetrahydrofuranyl, 1-ethoxyethyl or t-butyl; X represents: 1) —CH₂—CH₂—;2) —CH═CH—; or 3) —C≡C—; and R¹² represents: 1) a straight-chain C₁₋₁₂alkyl group or a branched C₃₋₁₄ alkyl group; 2) -Z-Ar²; wherein Z hasthe same meaning as defined above; and Ar² represents phenyl,α-naphthyl, β-naphthyl, or at least one chlorine, bromine, fluorine,iodine, trifluoromethyl, a C₁₋₄ alkyl group, nitro, cyano, methoxy,phenyl or phenoxy-substituted phenyl, or 3) —C_(t)H_(2t)OR¹⁴; whereinC_(t)H_(2t) has the same meaning as defined above; and R¹⁴ represents astraight-chain C₁₋₆ alkyl group, a branched C₃₋₆ alkyl, phenyl, or atleast one chlorine, bromine, fluorine, iodine, trifluoromethyl, an C₁₋₄alkyl, nitro, cyano, methoxy, phenyl or phenoxy-substituted phenyl,cyclopentyl, cyclohexyl, or a cyclopentyl or cyclohexyl substituted by 1to 4 straight-chain C₁₋₄ alkyl groups; 4) -Z-R³ wherein each of Z and R³has the same meaning as defined above; 5) —C_(t)H_(2t)—CH═C(R¹⁵)R¹⁶wherein C_(t)H_(2t) has the same meaning as defined above; and R¹⁵ andR¹⁶ independently represent hydrogen, methyl, ethyl, propyl or butylgroup; or 6) —C_(u)H_(2u)—C≡C—R¹⁷ wherein u represents an integer from 1to 7; C_(u)H_(2u) represents a straight-chain or branched alkylenegroup; and R¹⁷ represents a straight-chain C₁₋₆ alkyl group; and Erepresents hydrogen or —OR¹⁸ wherein R¹⁸ represents a C₁₋₁₂ acyl group,a C₇₋₁₅ aroyl group or R² (wherein R² has the same meaning as definedabove); and the formula is in the isomeric d-form, l-form or dl-form. 2.A therapeutic agent for renal failure comprising, as an active agent, a4,8-inter-m-phenylene prostaglandin I₂ derivative represented by thefollowing formula (I) or a pharmacologically acceptable salt thereof:

wherein: R¹ represents COOR² wherein R² represents hydrogen or apharmacologically acceptable positive ion; A represents: 1) —(CH₂)_(m)—;or 2) —CH₂—CH═CH— wherein m represents an integer from 1 to 3; Yrepresents hydrogen; B represents —X—C(R¹¹)(R¹²)OR¹³ wherein each of R¹¹and R¹³ represent hydrogen; X represents: 1) —CH═CH—; or 2) —C≡C—; andR¹² represents: 1) -Z-Ar²; 2) -Z-R³; or 3) —C_(u)H_(2u)—C≡C—R¹⁷ whereinZ represents a valence bond or a straight-chain or branched alkylenegroup represented by C_(t)H_(2t) where t represents an integer from 1 to6; Ar² represents phenyl, α-naphthyl, β-naphthyl, or at least onechlorine, bromine, fluorine, iodine, trifluoromethyl, a C₁₋₄ alkylgroup, nitro, cyano, methoxy, phenyl or phenoxy-substituted phenyl; R³represents a C₃₋₁₂ cycloalkyl group; u represents an integer from 1 to7; C_(u)H_(2u) represents a straight-chain or branched alkylene group;and R¹⁷ represents a straight-chain C₁₋₆ alkyl group; E represents —OH;and the formula is in the isomeric d-form, l-form or dl-form.
 3. Thetherapeutic agent for renal failure according to claim 1, wherein the4,8-inter-m-phenylene prostaglandin I₂ derivative is beraprost or a saltthereof.
 4. The therapeutic agent according to any one of claims 1 to 3,wherein the renal failure is chronic renal failure.
 5. The therapeuticagent according to any one of claims 1 to 3, wherein the causal diseaseof the renal failure is glomerulonephritis or diabetic nephropathy.
 6. Amethod for treatment of renal failure comprising administering aneffective amount of a 4,8-inter-m-phenylene prostaglandin I₂ derivativerepresented by the following formula (I) or a pharmacologicallyacceptable salt thereof:

wherein: R¹ represents: (A) COOR² wherein R² represents: 1) hydrogen ora pharmacologically acceptable positive ion; 2) a straight-chain C₁₋₁₂alkyl group or a branched C₃₋₁₄ alkyl group; 3) -Z-R³ wherein Zrepresents a valence bond or a straight-chain or branched alkylene grouprepresented by C_(t)H_(2t) where t represents an integer from 1 to 6;and R³ represents a C₃₋₁₂ cycloalkyl group unsubstituted or substitutedby 1 to 3 substituents of R⁴ where R⁴ is hydrogen or a C₁₋₅ alkyl group;4) —(CH₂CH₂O)_(n)CH₃ wherein n represents an integer from 1 to 5; 5)-Z-Ar¹ wherein Z has the same meaning as defined above; and Ar¹represents phenyl, α-naphthyl, β-naphthyl, 2-pyridyl, 3-pyridyl,4-pyridyl, α-furyl, β-furyl, α-thienyl, β-thienyl or substituted phenyl(wherein the substituted phenyl contains at least one substituent ofchlorine, bromine, fluorine, iodine, trifluoromethyl, a C₁₋₄ alkylgroup, nitro, cyano, methoxy, phenyl, phenoxy, p-acetamidobenzamide,—CH═N—NH—C(═O)—NH₂, —NH—C(═O)-Ph, —NH—C(═O)—CH₃ or —NH—C(═O)—NH₂); 6)—C_(t)H_(2t)COOR⁴ wherein each of C_(t)H_(2t) and R⁴ has the samemeaning as defined above; 7) —C_(t)H_(2t)N(R⁴)₂ wherein each ofC_(t)H_(2t) and R⁴ has the same meaning as defined above; 8)—CH(R⁵)—C(═O)—R⁶, wherein R⁵ represents hydrogen or benzoyl; and R⁶represents phenyl, p-bromophenyl, p-chlorophenyl, p-biphenyl,p-nitrophenyl, p-benzamidophenyl or 2-naphthyl; 9) —C_(p)H_(2p)—W—R⁷wherein W represents —CH═CH—, —CH═CR⁷— or —C≡C—; R⁷ represents hydrogenor a straight-chain or branched C₁₋₃₀ alkyl or aralkyl group; and prepresents an integer from 1 to 5; or 10) —CH(CH₂OR⁸)₂ wherein R³represents a C₁₋₃₀ alkyl or acyl group; (B) —CH₂OH; (C) —C(═O)N(R⁹)₂wherein R⁹ represents hydrogen or a straight-chain C₁₋₁₂ alkyl group, abranched C₃₋₁₂ alkyl group, a C₃₋₁₂ cycloalkyl group, a C₄₋₁₃cycloalkylalkylene group, a phenyl group, a substituted phenyl group(wherein the substitute or substituents are the same radicals as definedfor (A)-5) described above), a C₇₋₁₂ aralkyl group, or —SO₂R¹⁰ where R¹⁰represents a C₁₋₁₀ alkyl group, a C₃₋₁₂ cycloalkyl group, a phenylgroup, a substituted phenyl group (wherein the substitute orsubstituents are the same radicals as defined for (A)-5) describedabove) or a C₇₋₁₂ aralkyl group; provided that the two R⁹ radicals arethe same as or different from each other, but when one represents—SO₂R¹⁰, then the other does not represent —SO₂R¹⁰; or (D) —CH₂OTHP(wherein THP represents a tetrahydropyranyl group); A represents: 1)—(CH₂)_(m)—; 2) —CH═CH—CH₂—; 3) —CH₂—CH═CH—; 4) —CH₂—O—CH₂—; 5) —CH═CH—;6) —O—CH₂—; or 7) —C≡C— wherein m represents an integer from 1 to 3; Yrepresents hydrogen, a C₁₋₄ alkyl group, chlorine, bromine, fluorine,formyl, methoxy or nitro group; B represents —X—C(R¹¹)(R¹²)OR¹³ wherein:R¹¹ represents hydrogen or a C₁₋₄ alkyl group; R¹³ represents hydrogen,a C₁₋₁₄ acyl group, a C₆₋₁₅ aroyl group, tetrahydropyranyl,tetrahydrofuranyl, 1-ethoxyethyl or t-butyl; X represents: 1) —CH₂—CH₂—;2) —CH═CH—; or 3) —C≡C—; and R¹² represents: 1) a straight-chain C₁₋₁₂alkyl group or a branched C₃₋₁₄ alkyl group; 2) -Z-Ar²; wherein Z hasthe same meaning as defined above; and Ar² represents phenyl,α-naphthyl, β-naphthyl, or at least one chlorine, bromine, fluorine,iodine, trifluoromethyl, a C₁₋₄ alkyl group, nitro, cyano, methoxy,phenyl or phenoxy-substituted phenyl, or 3) —C_(t)H_(2t)OR¹⁴; whereinC_(t)H_(2t) has the same meaning as defined above; and R¹⁴ represents astraight-chain C₁₋₆ alkyl group, a branched C₃₋₆ alkyl, phenyl, or atleast one chlorine, bromine, fluorine, iodine, trifluoromethyl, an C₁₋₄alkyl, nitro, cyano, methoxy, phenyl or phenoxy-substituted phenyl,cyclopentyl, cyclohexyl, or a cyclopentyl or cyclohexyl substituted by 1to 4 straight-chain C₁₋₄ alkyl groups; 4) -Z-R³ wherein each of Z and R³has the same meaning as defined above; 5) —C_(t)H_(2t)—CH═C(R¹⁵)R⁶wherein C_(t)H_(2t) has the same meaning as defined above; and R¹⁵ andR¹⁶ independently represent hydrogen, methyl, ethyl, propyl or butylgroup; or 6) —C_(u)H_(2u)—C≡C—R¹⁷ wherein u represents an integer from 1to 7; C_(u)H_(2u) represents a straight-chain or branched alkylenegroup; and R¹⁷ represents a straight-chain C₁₋₆ alkyl group; and Erepresents hydrogen or —OR¹⁸ wherein R¹⁸ represents a C₁₋₁₂ acyl group,a C₇₋₁₅ aroyl group or R² (wherein R² has the same meaning as definedabove); and the formula is in the isomeric d-form, l-form or dl-form. 7.The method for treatment of renal failure according to claim 6, whereinthe 4,8-inter-m-phenylene prostaglandin I₂ derivative is represented bythe following formula (I):

wherein: R¹ represents COOR² wherein R² represents hydrogen or apharmacologically acceptable positive ion; A represents: 1) —(CH₂)_(m)—;or 2) —CH₂—CH═CH— wherein m represents an integer from 1 to 3; Yrepresents hydrogen; B represents —X—C(R¹¹)(R¹²)OR¹³ wherein each of R¹¹and R¹³ represent hydrogen; X represents: 1) —CH═CH—; or 2) —C≡C—; andR¹² represents: 1) -Z-Ar²; 2) -Z-R³; or 3) —C_(u)H_(2u)—C≡C—R¹⁷ whereinZ represents a valence bond or a straight-chain or branched alkylenegroup represented by C_(t)H_(2t) where t represents an integer from 1 to6; Ar² represents phenyl, α-naphthyl, β-naphthyl, or at least onechlorine, bromine, fluorine, iodine, trifluoromethyl, a C₁₋₄ alkylgroup, nitro, cyano, methoxy, phenyl or phenoxy-substituted phenyl; R³represents a C₃₋₁₂ cycloalkyl group; u represents an integer from 1 to7; C_(u)H_(2u) represents a straight-chain or branched alkylene group;and R¹⁷ represents a straight-chain C₁₋₆ alkyl group; E represents —OH;and the formula is in the isomeric d-form, l-form or dl-form.
 8. Themethod for treatment of renal failure according to claim 6, wherein the4,8-inter-m-phenylene prostaglandin I₂ derivative is beraprost or a saltthereof.
 9. The method for treatment of renal failure according to anyone of claims 6 to 8, wherein the renal failure is chronic renalfailure.
 10. The method for treatment of renal failure according to anyone of claims 6 to 8, wherein the causal disease of the renal failure isglomerulonephritis or diabetic nephropathy.